Transcriptional Activation of Regenerative Hematopoiesis via Vascular Niche Sensing
Transcriptional Activation of Regenerative Hematopoiesis via Vascular Niche Sensing
Abstract Transition between activation and quiescence programs in hematopoietic stem and progenitor cells (HSC/HSPCs) is perceived to be governed intrinsically and by microenvironmental co-adaptation. However, HSC programs dictating both transition and adaptability, remain poorly defined. Single cell multiome analysis divulging differential transcriptional activity between distinct HSPC states, indicated for the exclusive absence of Fli-1 motif from quiescent HSCs. We reveal that Fli-1 activity is essential for HSCs during regenerative hematopoiesis. Fli-1 directs activation programs while manipulating cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche. During regenerative conditions, Fli-1 presets and enables propagation of niche-derived Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional HSC impairments in the absence of Fli-1. Applying FLI-1 modified-mRNA transduction into lethargic adult human mobilized HSPCs, enables their vigorous niche-mediated expansion along with superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immune regenerative medicine.
Liu Ying、Voisin Veronique、Booth Gregory T.、Xie Stephanie Z.、Hadland Brandon、Dick John E.、Rafii Shahin、Shieh Jae-Hung、Josefowicz Steven Z.、Badwe Chaitanya R.、Xiang Jenny Z.、Garcia-Prat Laura、Houghton Sean、Lin Yang、Seyedhassantehrani Negar、Trapnell Cole、Gomez-Salinero Jesus M.、Kaufmann Kerstin B.、Itkin Tomer、Redmond David、Murison Alex、Geng Fuqiang、Schreiner Ryan、Zangi Lior、Spencer Joel A.
Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicinePrincess Margaret Cancer Centre and Department of Molecular Genetics, University Health Network, University of TorontoDepartment of Genome Sciences, University of Washington School of Medicine USAPrincess Margaret Cancer Centre and Department of Molecular Genetics, University Health Network, University of TorontoClinical Research Division and Department of Pediatrics, Fred Hutchinson Cancer Research Center, University of Washington School of MedicinePrincess Margaret Cancer Centre and Department of Molecular Genetics, University Health Network, University of TorontoDivision of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicineDivision of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicineDepartment of Pathology and Laboratory MedicineDivision of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicineGenomics Resources Core FacilityPrincess Margaret Cancer Centre and Department of Molecular Genetics, University Health Network, University of TorontoDivision of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicineDivision of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicineDepartment of Bioengineering, NSF-CREST Center for Cellular and Biomolecular Machines, University of California MercedDepartment of Genome Sciences, University of Washington School of Medicine USADivision of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicinePrincess Margaret Cancer Centre and Department of Molecular Genetics, University Health Network, University of TorontoDivision of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicineDivision of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicinePrincess Margaret Cancer Centre and Department of Molecular Genetics, University Health Network, University of TorontoDivision of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicineDivision of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of MedicineCardiovascular Research Institute and Department of Genetics and Genomic Sciences, Black Family Stem Cell Institute, Icahn School of Medicine at Mount SinaiDepartment of Bioengineering, NSF-CREST Center for Cellular and Biomolecular Machines, University of California Merced
基础医学细胞生物学分子生物学
Liu Ying,Voisin Veronique,Booth Gregory T.,Xie Stephanie Z.,Hadland Brandon,Dick John E.,Rafii Shahin,Shieh Jae-Hung,Josefowicz Steven Z.,Badwe Chaitanya R.,Xiang Jenny Z.,Garcia-Prat Laura,Houghton Sean,Lin Yang,Seyedhassantehrani Negar,Trapnell Cole,Gomez-Salinero Jesus M.,Kaufmann Kerstin B.,Itkin Tomer,Redmond David,Murison Alex,Geng Fuqiang,Schreiner Ryan,Zangi Lior,Spencer Joel A..Transcriptional Activation of Regenerative Hematopoiesis via Vascular Niche Sensing[EB/OL].(2025-03-28)[2025-05-11].https://www.biorxiv.org/content/10.1101/2023.03.27.534417.点此复制
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